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Methotrexate

Drug Information

Methotrexate (MTX) is a chemotherapy drug that interferes with folic acid activation, preventing cell reproduction. Methotrexate is used to treat some forms of cancer; severe, disabling psoriasis; and severe, active rheumatoid arthritis.

Note: Many of the interactions described below, in the text and in the Summary of Interactions, have been reported only for specific chemotherapeutic drugs, and may not apply to other chemotherapeutic drugs. There are many unknowns concerning interactions of nutrients, herbs, and chemotherapy drugs. People receiving chemotherapy who wish to supplement with vitamins, minerals, herbs, or other natural substances should always consult a physician.

Common brand names:

Rheumatrex Dose Pack, Trexall

Summary of Interactions with Vitamins, Herbs, & Foods

Replenish Depleted Nutrients

Magnesium and Potassium

The chemotherapy drug cisplatin may cause excessive loss of magnesium and potassium in the urine.1, 2 Preliminary reports suggest that both potassium and magnesium supplementation may be necessary to increase low potassium levels.3, 4 Severe magnesium deficiency caused by cisplatin therapy has been reported to result in seizures.5 Severe magnesium deficiency is a potentially dangerous medical condition that should only be treated by a doctor. People receiving cisplatin chemotherapy should ask their prescribing doctor to closely monitor magnesium and potassium status.

Glutathione, the main antioxidant found within cells, is frequently depleted in individuals on chemotherapy and/or radiation. Preliminary studies have found that intravenously injected glutathione may decrease some of the adverse effects of chemotherapy and radiation, such as diarrhea.7

In a preliminary trial, supplementation with a probiotic (Lactobacillus GG) reduced the frequency of severe diarrhea and the incidence of abdominal discomfort related to the use of 5-FU. The amount of Lactobacillus GG used was 10-20 billion organisms per day during the 24 weeks of chemotherapy.8

A modified form of vitamin A has been reported to work synergistically with chemotherapy in test tube research. Vitamin C appears to increase the effectiveness of chemotherapy in animals and with human breast cancer cells in test tube research.9 In a double-blind study, Japanese researchers found that the combination of vitamin E, vitamin C, and N-acetyl cysteine (NAC)-all antioxidants-protected against chemotherapy-induced heart damage without interfering with the action of the chemotherapy.10

A comprehensive review of antioxidants and chemotherapy leaves open the question of whether supplemental antioxidants definitely help people with chemotherapy side effects, but it clearly shows that antioxidants need not be avoided for fear that the actions of chemotherapy are interfered with.11 Although research remains incomplete, the idea that people taking chemotherapy should avoid antioxidants is not supported by scientific research.

High amounts of melatonin have been combined with a variety of chemotherapy drugs to reduce their side effects or improve drug efficacy. One study gave melatonin at night in combination with the drug triptorelin to men with metastatic prostate cancer.17 All of these men had previously become unresponsive to triptorelin. The combination decreased PSA levels-a marker of prostate cancer progression-in eight of fourteen patients, decreased some side effects of triptorelin, and helped nine of fourteen to live longer than one year. The outcome of this preliminary study suggests that melatonin may improve the efficacy of triptorelin even after the drug has apparently lost effectiveness.

Chemotherapy can injure cancer cells by creating oxidative damage. As a result, some oncologists recommend that patients avoid supplementing antioxidants if they are undergoing chemotherapy. Limited test tube research occasionally does support the idea that an antioxidant can interfere with oxidative damage to cancer cells.18 However, most scientific research does not support this supposition.

A modified form of vitamin A has been reported to work synergistically with chemotherapy in test tube research.19Vitamin C appears to increase the effectiveness of chemotherapy in animals20 and with human breast cancer cells in test tube research.21 In a double-blind study, Japanese researchers found that the combination of vitamin E, vitamin C, and N-acetyl cysteine (NAC)-all antioxidants-protected against chemotherapy-induced heart damage without interfering with the action of the chemotherapy.22

A comprehensive review of antioxidants and chemotherapy leaves open the question of whether supplemental antioxidants definitely help people with chemotherapy side effects, but it clearly shows that antioxidants need not be avoided for fear that the actions of chemotherapy are interfered with.23 Although research remains incomplete, the idea that people taking chemotherapy should avoid antioxidants is not supported by scientific research.

A new formulation of selenium (Seleno-Kappacarrageenan) was found to reduce kidney damage and white blood cell-lowering effects of cisplatin in one human study. However, the level used in this study (4,000 mcg per day) is potentially toxic and should only be used under the supervision of a doctor.24

Glutathione, the main antioxidant found within cells, is frequently depleted in individuals on chemotherapy and/or radiation. Preliminary studies have found that intravenously injected glutathione may decrease some of the adverse effects of chemotherapy and radiation, such as diarrhea.25

In a study of chemotherapy-induced mouth sores, six of nine patients who applied vitamin E directly to their mouth sores had complete resolution of the sores compared with one of nine patients who applied placebo.26Others have confirmed the potential for vitamin E to help people with chemotherapy-induced mouth sores.27Until more is known, if vitamin E is used in an attempt to reduce chemotherapy-induced mouth sores, it should be applied topically twice per day and should probably be in the tocopherol (versus tocopheryl) form.

In a preliminary study, the addition of oral vitamin E (300 IU per day) to cisplatin chemotherapy significantly reduced the incidence of drug-induced damage to the nervous system (neurotoxicity).28 A similar protective effect was seen in another trial in which 600 IU of vitamin E per day was used.29

Wheat Grass

In a preliminary trial, taking wheat grass in the amount of 60 ml (about 2 ounces) per day during chemotherapy reduced the incidence of certain chemotherapy-related side effects (including anemia and a decline in white blood cell counts) in women with breast cancer. Taking wheat grass did not appear to interfere with the anticancer effect of the chemotherapy. The chemotherapy used in this study was a combination of 5-fluorouracil, doxorubicin, and cyclophosphamide.30

Chemotherapy frequently causes mouth sores. In one trial, people were given approximately 400,000 IU of beta-carotene per day for three weeks and then 125,000 IU per day for an additional four weeks.31 Those taking beta-carotene still suffered mouth sores, but the mouth sores developed later and tended to be less severe than mouth sores that formed in people receiving the same chemotherapy without beta-carotene.

In a study of chemotherapy-induced mouth sores, six of nine patients who applied vitamin E directly to their mouth sores had complete resolution of the sores compared with one of nine patients who applied placebo.32 Others have confirmed the potential for vitamin E to help people with chemotherapy-induced mouth sores.33 Applying vitamin E only once per day was helpful to only some groups of patients in another trial,34 and not all studies have found vitamin E to be effective.35 Until more is known, if vitamin E is used in an attempt to reduce chemotherapy-induced mouth sores, it should be applied topically twice per day and should probably be in the tocopherol (versus tocopheryl) form.

Russian research has looked at using eleuthero with chemotherapy. One study of patients with melanoma found that chemotherapy was less toxic when eleuthero was given simultaneously. Similarly, women with inoperable breast cancer given eleuthero were reported to tolerate more chemotherapy.37 Eleuthero treatment was also associated with improved immune function in women with breast cancer treated with chemotherapy and radiation.38

Ginger can be helpful in alleviating nausea and vomiting caused by chemotherapy.39, 40 Ginger, as tablets, capsules, or liquid herbal extracts, can be taken in 500 mg amounts every two or three hours, for a total of 1 gram per day.

Patients with inoperable head and neck cancer were treated with a spleen peptide preparation (Polyerga®) in a double-blind trial during chemotherapy with cisplatin and 5-FU.41 The spleen preparation had a significant stabilizing effect on certain white blood cells. People taking it also experienced stabilized body weight and a reduction in the fatigue and inertia that usually accompany this combination of chemotherapy agents.

Irradiation treatment, especially of head and neck cancers, frequently results in changes to normal taste sensation.42, 43 Zinc supplementation may be protective against taste alterations caused or exacerbated by irradiation. A double-blind trial found that 45 mg of zinc sulfate three times daily reduced the alteration of taste sensation during radiation treatment and led to significantly greater recovery of taste sensation after treatment was concluded.44

Support Medicine

High amounts of melatonin have been combined with a variety of chemotherapy drugs to reduce their side effects or improve drug efficacy. One study gave melatonin at night in combination with the drug triptorelin to men with metastatic prostate cancer.45 All of these men had previously become unresponsive to triptorelin. The combination decreased PSA levels-a marker of prostate cancer progression-in eight of fourteen patients, decreased some side effects of triptorelin, and helped nine of fourteen to live longer than one year. The outcome of this preliminary study suggests that melatonin may improve the efficacy of triptorelin even after the drug has apparently lost effectiveness.

Milk thistle's major flavonoids, known collectively as silymarin, have shown synergistic actions with the chemotherapy drugs cisplatin and doxorubicin (Adriamycin®) in test tubes.46 Silymarin also offsets the kidney toxicity of cisplatin in animals.47 Silymarin has not yet been studied in humans treated with cisplatin. There is some evidence that silymarin may not interfere with some chemotherapy in humans with cancer.48

The mushroom Coriolus versicolor contains an immune-stimulating substance called polysaccharide krestin, or PSK. PSK has been shown in several studies to help cancer patients undergoing chemotherapy. One study involved women with estrogen receptor-negative breast cancer. PSK combined with chemotherapy significantly prolonged survival time compared with chemotherapy alone.49 Another study followed women with breast cancer who were given chemotherapy with or without PSK. The PSK-plus-chemotherapy group had a 25% better chance of survival after ten years compared with those taking chemotherapy without PSK.50 Another study investigated people who had surgically removed colon cancer. They were given chemotherapy with or without PSK. Those given PSK had a longer disease-free period and longer survival time.51 Three grams of PSK were taken orally each day in these studies.

Although PSK is rarely available in the United States, hot-water extract products made from Coriolus versicolor mushrooms are available. These products may have activity related to that of PSK, but their use with chemotherapy has not been studied.

Explanation Required

In cancer treatment, methotrexate works by blocking activation of folic acid. Folic acid-containing supplements may interfere with methotrexate therapy in people with cancer.53 Methotrexate therapy can lead to folic acid deficiency. People using methotrexate for cancer treatment should ask their prescribing doctor before using any folic acid-containing supplements. There is no concern about folic acid supplementation for people with cancer using chemotherapy drugs other than methotrexate.

Until recently, it was believed that methotrexate helped people with rheumatoid arthritis also by interfering with folic acid metabolism. However, this is not necessarily so, as some studies have shown that folic acid supplementation in amounts ranging from 5-50 mg per week did not alter the efficacy of methotrexate in the treatment of rheumatoid arthritis.54, 55, 56 Many doctors now believe that people with rheumatoid arthritis taking methotrexate should supplement large amounts of folic acid. In separate double-blind trials, 5 mg per week of folic acid and 2.5-5 mg per week of folinic acid (an activated form of folic acid) have substantially reduced side effects of methotrexate without interfering with the therapeutic action in rheumatoid patients.57, 58 Folic or folinic acid was taken at a different time from methotrexate and sometimes only five days per week. Daily (as opposed to weekly) supplementation with folic acid (5 mg per day for 13 days) was found to reduce blood levels of methotrexate;59 however, the researchers in this study suggest that the reduction in blood methotrexate levels by folic acid does not necessarily mean that the folic acid is interfering with the therapeutic action of the drug. It is possible that the lower blood levels of methotrexate are simply an indication that the drug is being taken up more rapidly by the cells as a result of folic acid supplementation. In most of the studies cited here, folic acid supplementation was begun 24 hours after the administration of methotrexate. Because of the uncertainty regarding this interaction, persons taking methotrexate for rheumatoid arthritis who are considering supplementation with folic acid should first consult with their doctor.

People who are prescribed methotrexate to treat severe psoriasis experience fewer side effects if they also supplement high amounts (5 mg per day) of folic acid.60 As is the case with methotrexate and rheumatoid arthritis, supplementing folic acid did not interfere with the activity of methotrexate. Such high levels of folic acid should not be taken without clinical supervision.

Echinacea is a popular immune-boosting herb that has been investigated for use with chemotherapy. One study investigated the actions of cyclophosphamide, echinacea, and thymus gland extracts to treat advanced cancer patients. Although small and uncontrolled, this trial suggested that the combination modestly extended the life span of some patients with inoperable cancers.61 Signs of restoration of immune function were seen in these patients.

Many chemotherapy drugs can cause diarrhea, lack of appetite, vomiting, and damage to the gastrointestinal tract. Recent anti-nausea prescription medications are often effective. Nonetheless, nutritional deficiencies still occur.62 It makes sense for people undergoing chemotherapy to take a high-potency multivitamin-mineral to protect against deficiencies.

Chemotherapy can injure cancer cells by creating oxidative damage. As a result, some oncologists recommend that patients avoid supplementing antioxidants if they are undergoing chemotherapy. Limited test tube research occasionally does support the idea that an antioxidant can interfere with oxidative damage to cancer cells.63 However, most scientific research does not support this supposition.

A modified form of vitamin A has been reported to work synergistically with chemotherapy in test tube research. Vitamin C combined with Vitamin K3 appears to increase the effectiveness of chemotherapy in animals64 and with human breast cancer cells in test tube research.65 In a double-blind study, Japanese researchers found that the combination of vitamin E, vitamin C, and N-acetyl cysteine (NAC)-all antioxidants-protected against chemotherapy-induced heart damage without interfering with the action of the chemotherapy.66

A comprehensive review of antioxidants and chemotherapy leaves open the question of whether supplemental antioxidants definitely help people with chemotherapy side effects, but it clearly shows that antioxidants need not be avoided for fear that the actions of chemotherapy are interfered with.67 Although research remains incomplete, the idea that people taking chemotherapy should avoid antioxidants is not supported by scientific research.

The Drug-Nutrient Interactions table may not include every possible interaction. Taking medicines with meals, on an empty stomach, or with alcohol may influence their effects. For details, refer to the manufacturers' package information as these are not covered in this table. If you take medications, always discuss the potential risks and benefits of adding a new supplement with your doctor or pharmacist.

25. De Maria D, Falchi AM, Venturino P. Adjuvant radiotherapy of the pelvis with or without reduced glutathione: a randomized trial in patients operated on for endometrial cancer. Tumori 1992;78:374-6.

Please read the disclaimer about the limitations of the information provided here. Do NOT rely solely on the information in this article. The Aisle7 knowledgebase does not contain every possible interaction.

The information presented in Aisle7 is for informational purposes only. It is based on scientific studies (human, animal, or in vitro), clinical experience, or traditional usage as cited in each article. The results reported may not necessarily occur in all individuals. For many of the conditions discussed, treatment with prescription or over-the-counter medication is also available. Consult your doctor, practitioner, and/or pharmacist for any health problem and before using any supplements or before making any changes in prescribed medications. Information expires June 2016.

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